tbuckley/cabot-search huggingface dataset:
P659: BUPARLISIB A PROMISING THERAPEUTIC APPROACH IN CHRONIC MYELOID LEUKEMIA RESISTANT TO IMATINIB
Authors: Raquel Alves, Inês Silva, Maria Inês Costa, Beatriz Lapa, Joana Jorge, Ana Cristina Gonçalves, Ana Bela Sarmento-Ribeiro
Journal: HemaSphere (2023)

Background: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the BCR-ABL oncoprotein, which has deregulated tyrosine kinase activity. Despite a high response rate to tyrosine kinase inhibitors, such as imatinib (IMA), some patients develop resistance to treatment. Several mechanisms are involved in IMA resistance and alternative signaling pathways are activated by the BCR-ABL oncoprotein, including the PI3K/AKT/mTOR pathway, increasing cell survival and resistance to apoptosis. Thus, the identification of new therapeutic targets that enable new alternatives to the treatment of CML-resistant patients is extremely important. Aims: Thus, this work aimed to evaluate the therapeutic potential of Buparlisib (BKM 120), a PI3K inhibitor, in in vitro models of CML sensitive and resistant to IMA. Methods: The study was carried out in an IMA-sensitive CML cell line, K-562 cells, and two IMA-resistant cell lines, the K-562 RC and K-562 RD cells. Cell lines were incubated in the absence and presence of Buparlisib in a single dose and in a daily fractionated administration. Additionally, the combined effect of PI3K inhibitor with Imatinib was also evaluated in the three models. The metabolic activity was evaluated by the resazurin assay. Cell death was evaluated by flow cytometry (FC) using annexin V and 7-AAD staining and by cell morphology using light microscopy (Giemsa staining). The cell cycle was analyzed by FC using propidium iodide (PI)/RNase. The results were statistically analyzed and were considered significant when p<0.05. Results: The results showed that BKM-120 (Buparlisib) reduced metabolic activity in a time- and dose-dependent manner, with IC50 after 72h of 1.1μM in K-562 cells, 1.2μM in K-562 RC cells, and 1.0μM in K-562 RD cells. Fractionated administration of BKM-120 was shown to be beneficial compared to a single administration, but only in resistant lines. The combination of BKM-120 and IMA induced a synergistic effect in all three cell lines but was more pronounced in the resistant models. BKM-120 induced a cytotoxic effect through the activation of apoptosis and showed a cytostatic effect by blocking the cell cycle in the G2/M phase. Apoptotic cell death was confirmed by morphological analysis, with the observation of bleebling and cellular contraction in cells after BKM-120 exposure. Summary/Conclusion In conclusion, our results suggest that buparlisib could be a new therapeutic strategy in the treatment of CML, with the most promising results in the case of resistance to IMA. Keywords: PI3K, Targeted therapy, Chronic myeloid leukemia, Drug resistance
P576: PREVALENCE AND CLINICAL SIGNIFICANCE OF GERMLINE MUTATIONS IN ACUTE MYELOID LEUKEMIA PATIENTS - A SINGLE-CENTER EXPERIENCE
Authors: Sheraz Bashir, Victor Ling, Chrishthuka Kangatharan, Michelle Richardson, Seoksan Teh, Zafar Ullah, Nicola Gill, Jayne Chappells, Joanne King, Ioana Nitu-Whalley, Debo Ademokun, Andrew Hodson, Mahesh Prahladan
Journal: HemaSphere (2023)

Background: Acute myeloid leukemia (AML) is a heterogeneous disease with complex genetic landscape. Germline mutations have been identified in several AML patients and may have important implications for treatment and outcome. The recognition of germline predisposition to hematological cancers is becoming more prevalent. The increased use of high-throughput and whole genome sequencing is identifying a significant number of underlying germline mutations that cause such cancers. Aims: This study aimed to investigate the prevalence and clinical significance of germline mutations in a cohort of AML patients. Methods: We conducted a retrospective analysis of 51 AML patients who had been diagnosed and treated at the East Suffolk and North Essex foundation NHS trust. Patients were included in the study if they had a germline mutation in one of five genes: GATA2, DDX41, RUNX1, ETV6, or CEBPA. We collected clinical and genomic data for each patient, including their date of birth, date of diagnosis, germline mutation, other mutations, FISH status, karyotype status, ELN risk stratification category, date of last treatment, and date of death/still alive status. Results: Of the 51 patients, 13 had a germline mutation in one of the five genes of interest. The prevalence of germline mutations in our cohort was 25.5%. The most commonly identified mutations were CEBPA (30.8%) and RUNX1 (53.8%), with none of the patients being positive for GATA2. Most of the patients (12 out of 13) had additional somatic mutations and karyotype abnormalities, with varying degrees of complexity. Karyotype abnormalities, including trisomy 8 and translocations between chromosome 12 and chromosome 22, were observed in some patients. The 2022 ELN risk stratification category was adverse in 6 patients, intermediate in 6 patients, and favorable in 1 patient. Patients with germline mutations had a range of overall survival (OS) and progression-free survival (PFS) times, with some patients still alive at the time of data analysis. Summary/Conclusion: Our study highlights the prevalence of germline mutations in a significant proportion of AML patients, and these mutations may have important implications for diagnosis, risk stratification, and treatment. Although the ELN risk stratification was available for all patients, we acknowledge that there are other factors affecting clinical outcome, and further research is needed to validate our findings and to determine the optimal management strategies for AML patients with germline mutations. Further research is needed to better understand the role of germline mutations in AML and to develop more personalized approaches to treatment and management. Keywords: Genomics, Mutation status, Mutation analysis, Acute myeloid leukemia
Quality of life after patient-initiated vs physician-initiated response to symptom monitoring: the SYMPRO-Lung trial
Authors: Nicole E Billingy, Vashti N M F Tromp, Neil K Aaronson, Rianne J A Hoek, Harm Jan Bogaard, Bregje D Onwuteaka-Philipsen, Lonneke van de Poll-Franse, Jacqueline G Hugtenburg, José Belderbos, Annemarie Becker-Commissaris, Corina J G van den Hurk, Iris Walraven, N C van Walree, K de Jaeger, S Samii, W Y Lam-Wong, F Koppe, J A Stigt, G J M Herder, A Welling, O C J Schuurbiers-Siebers, J M Smit, A J Staal-van den Brekel, W K de Jong
Journal: JNCI Journal of the National Cancer Institute (2023)

Abstract Background Previous studies using patient-reported outcomes measures (PROMs) to monitor symptoms during and after (lung) cancer treatment used alerts that were sent to the health-care provider, although an approach in which patients receive alerts could be more clinically feasible. The primary aim of this study was to compare the effect of weekly PROM symptom monitoring via a reactive approach (patient receives alert) or active approach (health-care provider receives alert) with care as usual on health-related quality of life (HRQOL) at 15 weeks after start of treatment in lung cancer patients. Methods The SYMPRO–Lung trial is a multicenter randomized controlled trial using a stepped wedge design. Stage I-IV lung cancer patients in the reactive and active groups reported PROM symptoms weekly, which were linked to a common alerting algorithm. HRQOL was measured by the EORTC QLQ-C30 at baseline and after 15 weeks. Linear regression analyses and effect size estimates were used to assess mean QOL–C30 change scores between groups, accounting for confounding. Results A total of 515 patients were included (160 active group, 89 reactive group, 266 control group). No differences in HRQOL were observed between the reactive and active group (summary score: unstandardized beta [B] = 0.51, 95% confidence interval [CI] = -3.22 to 4.24, Cohen d effect size [ES] = 0.06; physical functioning: B = 0.25, 95% CI = -5.15 to 4.64, ES = 0.02). The combined intervention groups had statistically and clinically significantly better mean change scores on the summary score (B = 4.85, 95% CI = 1.96 to 7.73, ES = 0.57) and physical functioning (B = 7.00, 95% CI = 2.90 to 11.09, ES = 0.71) compared with the control group. Conclusions Weekly PRO symptom monitoring statistically and clinically significantly improves HRQOL in lung cancer patients. The logistically less intensive, reactive approach may be a better fit for implementation.
Cell membrane-camouflaged bufalin targets NOD2 and overcomes multidrug resistance in pancreatic cancer
Authors: Wei Zhang, Yibao Fan, Jinze Zhang, Dan Shi, Jiahui Yuan, Milad Ashrafizadeh, Wei Li, Man Hu, A.M. Abd El-Aty, Ahmet Hacimuftuoglu, Michael Linnebacher, Yongxian Cheng, Weiguang Li, Shuo Fang, Peng Gong, Xianbin Zhang
Journal: Drug Resistance Updates (2023)

Multidrug resistance in pancreatic cancer poses a significant challenge in clinical treatment. Bufalin (BA), a compound found in secretions from the glands of toads, may help overcome this problem. However, severe cardiotoxicity thus far has hindered its clinical application. Hence, the present study aimed to develop a cell membrane-camouflaged and BA-loaded polylactic-co-glycolic acid nanoparticle (CBAP) and assess its potential to counter chemoresistance in pancreatic cancer.The toxicity of CBAP was evaluated by electrocardiogram, body weight, distress score, and nesting behavior of mice. In addition, the anticarcinoma activity and underlying mechanism were investigated both in vitro and in vivo.CBAP significantly mitigated BA-mediated acute cardiotoxicity and enhanced the sensitivity of pancreatic cancer to several clinical drugs, such as gemcitabine, 5-fluorouracil, and FOLFIRINOX. Mechanistically, CBAP directly bound to nucleotide-binding and oligomerization domain containing protein 2 (NOD2) and inhibited the expression of nuclear factor kappa-light-chain-enhancer of activated B cells. This inhibits the expression of ATP-binding cassette transporters, which are responsible for chemoresistance in cancer cells.Our findings indicate that CBAP directly inhibits NOD2. Combining CBAP with standard-of-care chemotherapeutics represents a safe and efficient strategy for the treatment of pancreatic cancer.
Precision Nutrition: The Hype Is Exceeding the Science and Evidentiary Standards Needed to Inform Public Health Recommendations for Prevention of Chronic Disease
Authors: Regan L. Bailey, Patrick J. Stover
Journal: Annual Review of Nutrition (2023)

As dietary guidance for populations shifts from preventing deficiency disorders to chronic disease risk reduction, the biology supporting such guidance becomes more complex due to the multifactorial risk profile of disease and inherent population heterogeneity in the diet–disease relationship. Diet is a primary driver of chronic disease risk, and population-based guidance should account for individual responses. Cascading effects on evidentiary standards for population-based guidance are not straightforward. Precision remains a consideration for dietary guidance to prevent deficiency through the identification of population subgroups with unique nutritional needs. Reducing chronic disease through diet requires greater precision in ( a) establishing essential nutrient needs throughout the life cycle in both health and disease; ( b) considering effects of nutrients and other food substances on metabolic, immunological, inflammatory, and other physiological responses supporting healthy aging; and ( c) considering healthy eating behaviors. Herein we provide a template for guiding population-based eating recommendations for reducing chronic diseases in heterogenous populations.
TDP-43-regulated cryptic RNAs accumulate in Alzheimer’s disease brains
Authors: Virginia Estades Ayuso, Sarah Pickles, Tiffany Todd, Mei Yue, Karen Jansen-West, Yuping Song, Jesús González Bejarano, Bailey Rawlinson, Michael DeTure, Neill R. Graff-Radford, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Dennis W. Dickson, Keith A. Josephs, Leonard Petrucelli, Mercedes Prudencio
Journal: Molecular Neurodegeneration (2023)

Abstract Background Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer’s disease (AD). Approximately, 30–70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis. Methods To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively. Results We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2 , KCNQ2 , UNC13A , CAMK2B , and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls. Conclusions Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP.
Causes and Clinical Sequelae of Riboflavin Deficiency
Authors: Helene McNulty, Kristina Pentieva, Mary Ward
Journal: Annual Review of Nutrition (2023)

Riboflavin, in its cofactor forms flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), plays fundamental roles in energy metabolism, cellular antioxidant potential, and metabolic interactions with other micronutrients, including iron, vitamin B6, and folate. Severe riboflavin deficiency, largely confined to low-income countries, clinically manifests as cheilosis, angular stomatitis, glossitis, seborrheic dermatitis, and severe anemia with erythroid hypoplasia. Subclinical deficiency may be much more widespread, including in high-income countries, but typically goes undetected because riboflavin biomarkers are rarely measured in human studies. There are adverse health consequences of low and deficient riboflavin status throughout the life cycle, including anemia and hypertension, that could contribute substantially to the global burden of disease. This review considers the available evidence on causes, detection, and consequences of riboflavin deficiency, ranging from clinical deficiency signs to manifestations associated with less severe deficiency, and the related research, public health, and policy priorities.
Osteocalcin: A Multifaceted Bone-Derived Hormone
Authors: Gerard Karsenty
Journal: Annual Review of Nutrition (2023)

Together, loss- and gain-of-function experiments have identified the bone-derived secreted molecule osteocalcin as a hormone with a broad reach in rodents and primates. Following its binding to one of three receptors, osteocalcin exerts a profound influence on various aspects of energy metabolism as well as steroidogenesis, neurotransmitter biosynthesis and thereby male fertility, electrolyte homeostasis, cognition, the acute stress response, and exercise capacity. Although this review focuses mostly on the regulation of energy metabolism by osteocalcin, it also touches on its other functions. Lastly, it proposes what could be a common theme between the functions of osteocalcin and between these functions and the structural functions of bone.
A Biodegradable Nucleotide Coordination Polymer for Enhanced NSCLC Therapy in Combination with Metabolic Modulation
Authors: Jie Zhang, Xiaoyang Li, Yue Yin, Guoliang Cao, Hai Wang
Journal: Advanced Healthcare Materials (2023)

Abstract Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs) in the treatment of non‐small cell lung cancer (NSCLC) still face challenges of acquired resistance and non‐negligible side effects. To overcome these limitations, a biodegradable coordination polymer using guanine deoxynucleotide and ferrous iron (dGNP) is developed for targeted delivery of EGFR‐TKIs. dGNPs can efficiently target nucleoside transporters in tumor cells that are regulated by fasting‐mimicking diet (FMD). Meanwhile, FMD can augment the therapeutic efficacy of EGFR‐TKIs by suppressing EGFR tyrosine kinase phosphorylation and related downstream pathways. In vivo results demonstrate that EGFR‐TKIs‐laden dGNPs combined with FMD treatment exhibit superior antitumor efficacy and reduced side effect. This study provides an innovative approach to enhance the therapeutic efficacy of EGFR‐TKIs through nucleotide nanocarrier and metabolic modulation.
Publisher Correction: Human memory B cells show plasticity and adopt multiple fates upon recall response to SARS-CoV-2
Authors: Yves Zurbuchen, Jan Michler, Patrick Taeschler, Sarah Adamo, Carlo Cervia, Miro E. Raeber, Ilhan E. Acar, Jakob Nilsson, Klaus Warnatz, Michael B. Soyka, Andreas E. Moor, Onur Boyman
Journal: Nature Immunology (2023)
Heat is associated with short-term increases in household food insecurity in 150 countries and this is mediated by income
Authors: Carolin Kroeger
Journal: Nature Human Behaviour (2023)

Abstract Rising temperatures are expected to stall progress on food insecurity by reducing agricultural yields in the coming decades. But hot periods may also increase food insecurity within days when it gets too hot to work and earn an income, thus limiting households’ capability to purchase food. Here I exploit variations in heat levels during a household survey spanning 150 countries in a quasi-natural experiment to show that particularly hot weeks are associated with higher chances of food insecurity among households (0.5767, 95% confidence interval 0.2958–0.8576, t = 4.024, d.f. = 427,816, P &lt; 0.001). This association is mediated by reductions in income and health for households and the effects are stronger in countries with lower incomes and more agricultural or precarious forms of employment. The results highlight the importance of labour market disruptions for food insecurity and suggest integration of these concerns into heat action plans and food programmes.
Metformin, Cognitive Function, and Changes in the Gut Microbiome
Authors: Marisel Rosell-Díaz, José Manuel Fernández-Real
Journal: Endocrine Reviews (2023)

Abstract The decline in cognitive function and the prevalence of neurodegenerative disorders are among the most serious threats to health in old age. The prevalence of dementia has reached 50 million people worldwide and has become a major public health problem. The causes of age-related cognitive impairment are multiple, complex, and difficult to determine. However, type 2 diabetes (T2D) is linked to an enhanced risk of cognitive impairment and dementia. Human studies have shown that patients with T2D exhibit dysbiosis of the gut microbiota. This dysbiosis may contribute to the development of insulin resistance and increased plasma lipopolysaccharide concentrations. Metformin medication mimics some of the benefits of calorie restriction and physical activity, such as greater insulin sensitivity and decreased cholesterol levels, and hence may also have a positive impact on aging in humans. According to recent human investigations, metformin might partially restore gut dysbiosis related to T2D. Likewise, some studies showed that metformin reduced the risk of dementia and improved cognition, although not all studies are concordant. Therefore, this review focused on those human studies describing the effects of metformin on the gut microbiome (specifically the changes in taxonomy, function, and circulating metabolomics), the changes in cognitive function, and their possible bidirectional implications.
GATK-gCNV enables the discovery of rare copy number variants from exome sequencing data
Authors: Mehrtash Babadi, Jack M. Fu, Samuel K. Lee, Andrey N. Smirnov, Laura D. Gauthier, Mark Walker, David I. Benjamin, Xuefang Zhao, Konrad J. Karczewski, Isaac Wong, Ryan L. Collins, Alba Sanchis-Juan, Harrison Brand, Eric Banks, Michael E. Talkowski
Journal: Nature Genetics (2023)
The Placenta: A Maternofetal Interface
Authors: Kimberly O'Brien, Yiqin Wang
Journal: Annual Review of Nutrition (2023)

The placenta is the gatekeeper between the mother and the fetus. Over the first trimester of pregnancy, the fetus is nourished by uterine gland secretions in a process known as histiotrophic nutrition. During the second trimester of pregnancy, placentation has evolved to the point at which nutrients are delivered to the placenta via maternal blood (hemotrophic nutrition). Over gestation, the placenta must adapt to these variable nutrient supplies, to alterations in maternal physiology and blood flow, and to dynamic changes in fetal growth rates. Numerous questions remain about the mechanisms used to transport nutrients to the fetus and the maternal and fetal determinants of this process. Growing data highlight the ability of the placenta to regulate this process. As new technologies and omics approaches are utilized to study this maternofetal interface, greater insight into this unique organ and its impact on fetal development and long-term health has been obtained.
Postacute sequelae of COVID-19 at 2 years
Authors: Benjamin Bowe, Yan Xie, Ziyad Al-Aly
Journal: Nature Medicine (2023)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to postacute sequelae in multiple organ systems, but evidence is mostly limited to the first year postinfection. We built a cohort of 138,818 individuals with SARS-CoV-2 infection and 5,985,227 noninfected control group from the US Department of Veterans Affairs and followed them for 2 years to estimate the risks of death and 80 prespecified postacute sequelae of COVID-19 (PASC) according to care setting during the acute phase of infection. The increased risk of death was not significant beyond 6 months after infection among nonhospitalized but remained significantly elevated through the 2 years in hospitalized individuals. Within the 80 prespecified sequelae, 69% and 35% of them became not significant at 2 years after infection among nonhospitalized and hospitalized individuals, respectively. Cumulatively at 2 years, PASC contributed 80.4 (95% confidence interval (CI): 71.6-89.6) and 642.8 (95% CI: 596.9-689.3) disability-adjusted life years (DALYs) per 1,000 persons among nonhospitalized and hospitalized individuals; 25.3% (18.9-31.0%) and 21.3% (18.2-24.5%) of the cumulative 2-year DALYs in nonhospitalized and hospitalized were from the second year. In sum, while risks of many sequelae declined 2 years after infection, the substantial cumulative burden of health loss due to PASC calls for attention to the care needs of people with long-term health effects due to SARS-CoV-2 infection.